The skeletal muscle Ca2+ release channel, also known as the ryanodine receptor (RYR1), regulates[unreadable] the release of Ca2+ from sarcoplasmic reticulum (SR) stores and is mutated in human central core[unreadable] disease (CCD) and in the pharmacogenetic syndrome, malignant hyperthermia (MH). The[unreadable] mutations cluster in three regions of RYR1: region 1 from amino acids 35 to 614, region 2 from[unreadable] 2163 to 2459 and region 3 from 4647-4914. The MH mutations are located primarily in cytoplasmic[unreadable] regionsl and 2 while most of the CCD mutations are found in the transmembrane region 3. The[unreadable] working hypotheses to be tested in this project are: a. Regions 1 and 2, located in the clamp[unreadable] domain, interact to allosterically stabilize a closed state of the channel, b. The MH mutations, by[unreadable] destabilizing this interaction, enhance the response of the channel (and hence muscle) to activators[unreadable] and elevated temperature, c. Enhanced RyR1 activity during exercise elevates endogenous[unreadable] cytokines that act as pyrogens (such as IL-6) and the subsequent increase in body temperature[unreadable] increases the probability of an MH response. To test these hypotheses, the following specific aims[unreadable] are proposed: A1. Define the effects of the MH/CCD mutations on the conformational changes in[unreadable] the clamp domain of RyR1 A2. Evaluate the effects of the MH/CCD mutations on the structural and[unreadable] contractile properties of the muscle. A3. Determine if the probability of exercise-induced MH[unreadable] responses and/or rhabdomyolysis is increased by elevated body temperature and/or increased[unreadable] endogenous IL-6 concentrations. These studies will use mice with MH/CCD mutations that have[unreadable] been generated in Projects 1 and 3.